A retrospective analysis of Pseudomonas aeruginosa bloodstream infections: prevalence, risk factors, and outcome in carbapenem-susceptible and -non-susceptible infections.

Background: Pseudomonas aeruginosa (PA) is a leading cause of nosocomial infections, and carbapenem non-susceptible strains are a major threat to patient safety. Methods: A single center, retrospective comparative analysis of carbapenem-non-susceptible PA (CnSPA) and carbapenem-susceptible PA (CSPA) bloodstream infections (BSIs) was conducted between January 1, 2007, and December 31, 2016. Prevalence and risk factors associated with CnSPA BSIs were examined. Results: The study enrolled 340 patients with PA BSIs; 30.0% (N = 101) of patients had CnSPA. High APACHE II scores (≥15), central venous catheterization, and delayed application of appropriate definitive therapy were independently associated with higher risk of mortality in PA BSIs. Multivariate analysis revealed that respiratory disease and exposure to carbapenems within the previous 90 days to onset of BSI were independent risk factors for acquisition of CnSPA BSIs. Overall all-cause 30-day mortality associated with PA BSIs was 26.8% (91/340). In addition, mortality was higher in patients with CnSPA than in those with CSPA (37.6% vs. 22.2%, respectively; P = 0.003). Corticosteroid therapy and delayed receipt of effective definitive therapy were independent risk factors for death from CnSPA BSIs. Conclusion: Increased incidence of CnSPA BSIs was observed during the study period, with higher mortality seen in patients with these infections. Respiratory disease and exposure to carbapenems were independent risk factors for development of CnSPA BSIs. Appropriate definitive therapy reduced mortality rates. BLBLIs were as effective as carbapenems as a treatment for PA BSIs.

Pharmacokinetics of high-dose extended-infusion meropenem during pulmonary exacerbation in adult cystic fibrosis patients: a case series.

This case series explored the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of meropenem (MEM) in adult cystic fibrosis (CF) patients hospitalized for a pulmonary exacerbation. From January 2015 to June 2016, all adult patients with cystic fibrosis (CF) and chronic pulmonary infection due to meropenem (MEM)-susceptible/intermediate Pseudomonas aeruginosa who received at least 48 h of MEM as an extended 3-hour infusion for treating a pulmonary exacerbation were enrolled. MEM plasma concentrations were determined by high-performance liquid chromatography. Six adult CF patients with a median age of 47 years were included in the study. MEM showed a high Vd (mean 45.98 L, standard deviation [SD] ±34.45). A minimal PK/PD target of 40% T > minimum inhibitory concentration (MIC) with respect to the MEM MIC of P. aeruginosa strains isolated from sputum during exacerbation was achieved in 5/6 patients (83%). MEM failed to achieve this target only in one patient, whose strain showed the highest MEM MIC in our cohort (8 mg/L). In all patients, MEM was well tolerated, and no adverse events were reported. In conclusion, high-dose, extended-infusion MEM during pulmonary exacerbation showed a high Vd in six adult CF patients with high median age, and was well tolerated.

Pathogenic role of interleukin-6 in the development of sepsis. Part II: Significance of anti-interleukin-6 and anti-soluble interleukin-6 receptor-alpha antibodies in a standardized murine contact burn model.

OBJECTIVE: The in vivo effects of anti-interleukin-6 (anti-IL-6) and anti-interleukin-6-alpha receptor (anti-IL-6R) monoclonal antibodies on immune response and survival rate of a burn with subsequent infection were assessed. SUBJECTS: Ten-week-old C 57 BL/6J mice received a standardized contact burn; 48 hrs later endotoxin (LPS) was injected intraperitoneally to induce systemic inflammation. Ten different groups were studied. Groups I-IV sustained a burn and/or a LPS-stimulus but did not receive any anti-cytokines and served as controls. Treatment groups V-X sustained the same injuries but also received anti-IL-6 and anti-IL-6R intravenously either before or after the LPS stimulus. In a further part of the study, a lethal dose of LPS was injected (LPS-LD(100) group) followed by an injection of anti-IL-6 antibody and/or anti-IL-6R antibody. MEASUREMENTS: Serum concentrations of IL-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and white blood cell and platelet counts were determined, and the survival rate over a 2-wk period was assessed. RESULTS: Treatment with anti-IL-6 slightly decreased the inflammatory response when it was given before or after LPS application. The inflammatory response was not decreased after treatment with anti-IL-6R. In the groups that received a combination of anti-IL-6 and anti-IL-6R, there was a significant reduction of the inflammatory response. This was more pronounced when the anti-cytokines were applied after LPS application. A significant reduction in mortality could be shown with both antibodies in the treatment groups and the groups that had received a lethal dose of LPS (LPS-LD(100) group). CONCLUSIONS: IL-6 has a low inflammatory potential, and IL-6R has no inflammatory potential by itself. In contrast, the IL-6/IL-6R complexes have a higher inflammatory potential. Mortality could be reduced by each antibody alone as well as by the combination, supporting the hypothesis that the inflammatory and lethal potentials of IL-6 are not identical. The study suggests that the use of antibodies against IL-6 or IL-6R is effective in the prevention of systemic inflammation in a murine burn model.

Resolution of infectious parameters after antimicrobial therapy in patients with ventilator-associated pneumonia.

Although recommended durations of antimicrobial therapy for ventilator-associated pneumonia (VAP) range from 7 to 21 d, these are not based on prospective studies and little is known about the resolution of symptoms after start of antibiotics. Resolution of these symptoms was investigated in 27 patients. VAP was diagnosed on clinical, radiographic, and microbiological criteria, including quantitative cultures of bronchoalveolar lavage. All patients received appropriate antibiotic therapy. Highest temperatures, leukocyte counts, Pa(O(2))/FI(O(2)) ratios, and semiquantitative cultures of endotracheal aspirates were recorded from start of therapy until Day 14. Resolution was defined as the first day that these parameters fulfilled the following definition: temperature < or = 38 degrees C, leukocytes < or = 10 x 10(9)/L, Pa(O(2))/FI(O(2)) ratio > or = 25 kPa, and no or +1 of bacterial growth of etiologic pathogens in cultures of endotracheal aspirate. VAP was caused by Enterobacteriaceae (n = 14), P. aeruginosa (n = 7), S. aureus (n = 6), H. influenzae (n = 3), and S. pneumoniae (n = 1). H. influenzae and S. pneumoniae were eradicated from tracheal aspirates, whereas Enterobacteriaceae, S. aureus, and P. aeruginosa persisted, despite in vitro susceptibility to antibiotics administered. Significant improvements were observed for all clinical parameters, most apparently within the first 6 d after start of antibiotics. Newly acquired colonization, especially with P. aeruginosa and Enterobacteriaceae, occurred in the second week of therapy. Six patients developed a recurrent episode of VAP, four of them with P. aeruginosa. Clinical responses to therapy for VAP occur within the first 6 d of therapy, endotracheal colonization with Gram-negative bacteria persists despite susceptibility to therapy, and acquired colonization usually occurs in the second week of therapy and frequently precedes a recurrent episode.

Evaluation of the safety of recombinant P-selectin glycoprotein ligand-immunoglobulin G fusion protein in experimental models of localized and systemic infection.

P-selectin is a major component in the early interaction between platelets, endothelial cells, and inflammatory cells in the initial phases of the innate immune response. The major ligand for P-selectin is P-selectin glycoprotein ligand-1 (PSGL-1) and this ligand is expressed on the surface of monocyte, lymphocyte, and neutrophil membranes. A truncated form of recombinant human P-selectin glycoprotein ligand-1 has been covalently linked to immunoglobulin G (rPSGL-Ig) and this fusion peptide functions as a competitive inhibitor of PSGL-1. As an inhibitor of neutrophil-endothelial cell adherence, rPSGL-Ig is in early clinical development for the treatment of ischemia reperfusion injury. To determine the potential for deleterious effects from inhibition in P-selectin-mediated neutrophil attachment in the presence of bacterial infection, the effects of therapeutic doses of rPSGL-Ig were tested in three standard laboratory sepsis models. The experimental models included: the murine systemic Listeria monocytogenes infection model, the Pseudomonas aeruginosa bacteremia model in neutropenic rats, and the cecal ligation and puncture (CLP)-induced peritonitis model in rats. Recombinant human PSGL-Ig had no adverse effects on mortality or immune clearance in systemic bacterial infection in any of the three infection models. The PSGL-1 inhibitor did significantly decrease local neutrophil infiltration and bacterial clearance in the peritoneum following CLP, but this did not increase the systemic levels of proinflammatory cytokines, the quantitative levels of bacteremia, or the overall mortality rate following CLP. The results indicate that rPSGL-Ig did not exacerbate infection in these experimental sepsis models.

Prostaglandin E2 receptor antagonist (SC-19220) treatment restores the balance to bone marrow myelopoiesis after burn sepsis.

BACKGROUND: Although prostaglandin E2 (PGE2) has been shown to be immunosuppressive, its role in the development of specific bone marrow myeloid lineages after thermal injury and sepsis has yet to be elucidated. The purpose of this study was to demonstrate that alterations in bone marrow progenitor proliferation favoring monocytopoiesis in burn sepsis can be restored by blocking the cellular interactions of PGE2. METHODS: A murine model of burn sepsis with and without treatment with SC-19220, a PGE2 receptor antagonist, was used to determine peripheral monocyte and neutrophil counts as well as the colony forming potential of colony-stimulating factor responsive bone marrow progenitors. RESULTS: Burn sepsis augmented the growth of the early colony-forming unit granulocyte-macrophage and monocyte progenitors and the number of circulating monocytes, whereas granulocyte progenitors and circulating neutrophils demonstrated an opposite response. Treatment with SC-19220 nearly reversed these alterations. CONCLUSION: These data indicate that abrogating PGE2's actions during burn sepsis can restore the balance in bone marrow granulocyte and monocyte production, further consolidating the pivotal role PGE2 plays in the pathogenesis of burn sepsis.

Differential distributions in tissues and efficacies of aztreonam and ceftazidime and in vivo bacterial morphological changes following treatment.

The differential tissue distributions of aztreonam and ceftazidime within fibrin clots infected with Pseudomonas aeruginosa, Enterobacter cloacae, and Serratia marcescens, their efficacies, and the in vivo bacterial morphological changes induced by these drugs were evaluated. Rabbits were given intravenously a single dose of 100 mg of either agents/kg of body weight. In the cores of the clots, the peak levels of both drugs were much lower than those observed in the peripheries and in serum. Aztreonam's half-lives within the peripheries and in the cores of the fibrin clots were up to six times higher than observed in serum, while ceftazidime's half-lives in clots were twice that observed in serum. This resulted in a much greater penetration ratio for aztreonam than for ceftazidime. Both drugs controlled the growth of P. aeruginosa in vivo, but E. cloacae and S. marcescens responded better to ceftazidime. Morphological changes were more abundant in the peripheries than in the cores of the clots. In the control group, P. aeruginosa's morphology in the cores was different than that in the peripheries of the clots. Against P. aeruginosa, aztreonam did induce morphological changes in the cores while ceftazidime did not. Electron microscopic studies revealed that morphological changes associated with aztreonam seemed different than those of ceftazidime. Along with elongation of bacteria, more bow tie and herniated bacteria were observed with aztreonam. Though both agents selectively affect PBP 3, as manifested by elongated bacteria, they induce in the peripheries of the clots thickening, breaks, and detachment in bacterial cell walls, alterations which are generally associated with antibiotics affecting PBP 1a and 1b.

[Critical serum concentration of antibiotics. A therapeutic tool and means of comparative evaluation]. / La concentration sérique critique des antibiotiques. Outil thérapeutique et moyen d'évaluation comparative.

It is difficult to predict the clinical activity of antibiotics solely on the basis of in vitro data. Experimental models measuring the relationship between serum concentration and in vivo activity are essential for comparing the activity of different compounds currently available. The critical serum concentration can be used to compare the intrinsic activity of antibiotics on a given bacterial strain. When compared with the minimal inhibiting concentration measured in vitro, "activity loss" can be determined for each antibiotic placed in contact with bacteria in an infected tissue. The relevance of this therapeutic tool in comparison with other methods is discussed.

Effects of granulocyte colony-stimulating factor in modifying mortality from Pseudomonas aeruginosa pneumonia after hemorrhage.

BACKGROUND AND METHODS: Alterations in immune function occurring after hemorrhage and trauma may contribute to the high occurrence rates of nosocomial pneumonia, multiorgan system failure, morbidity, and mortality in this setting. Therapy with granulocyte colony-stimulating factor (G-CSF) can increase neutrophil numbers and function, and enhance resistance to infection in experimental and clinical settings associated with abnormal immune function. To investigate whether treatment with G-CSF could increase resistance to pneumonia after hemorrhage, we bled mice 30% of the blood volume and treated them with various doses of G-CSF, starting either immediately or 2 days after hemorrhage. Pseudomonas aeruginosa pneumonia was induced by the intratracheal instillation of 2 x 10(7) colony-forming units of P. aeruginosa 4 days after blood loss, and mortality was assessed over the next 7 days. RESULTS: Treatment of mice with 100 or 500 micrograms/kg/day G-CSF, but not with 50 micrograms/kg/day, resulted in significant increases in the numbers of circulating polymorphonuclear cells. Platelet counts significantly decreased in mice given 500 micrograms/kg/day G-CSF. Mice given 100 micrograms/kg/day G-CSF starting 2 days after blood loss had improved outcome compared with vehicle-treated controls (38% survival rate in the G-CSF treated group vs. 8% in controls, p less than .05). There also was a trend toward an improved survival rate in mice treated with 50 micrograms/kg/day G-CSF for 4 days after hemorrhage (46% survival rate in G-CSF treated vs. 17% in controls). CONCLUSIONS: G-CSF prophylactically administered after hemorrhage can improve survival from pneumonia due to P. aeruginosa. However, the protection afforded by G-CSF was highly dependent on the dosing schedule used.

Preventive effect of several drugs against Pseudomonas aeruginosa infection and the toxicity of combined tumor necrosis factor with lipopolysaccharide: relationship between lethality and the arachidonic cascade.

The participation of tumor necrosis factor (TNF) and lipopolysaccharide (LPS) in Pseudomonas aeruginosa (Pa) infection was examined. The lethal challenge of Pa or TNF and LPS injection could be prevented by pretreatment with anti-TNF antibody, polymyxin B, ONO 1078, or Shosaiko-to. The combined effects of TNF and LPS may be deeply related to the lethality of Pa infection. The activities of leukotriene(LT) C4/D4/E4 or platelet activating factor (PAF) were also related to the lethality of Pa infection, probably due to the subsequently produced TNF which acts in combination with LPS. Activating the host defence mechanism with biological response modifiers like Chinese medicines was effective against Pa infection. One mechanism could involve an activity as an LT inhibitor or PAF antagonist. Following the administration of TNF and/or LPS, the serum levels of arachidonic cascade products underwent various changes. With a combination of TNF and LPS, there was a synergistic increment of prostaglandins, thromboxane, and LT. Following pretreatment with Shosaiko-to, suppression of LTs was dominant even with the combination of TNF and LPS, which might be related to the lethality of the infection or combined TNF with LPS.

[Azlocillin in the treatment of pulmonary infections in patients with cystic fibrosis: plasma concentrations and therapeutic indications]. / L'azlocillina nel trattamento delle infezioni polmonari dei pazienti affetti da fibrosi cistica: concentrazioni plasmatiche e indicazioni terapeutiche.

Azlocillin plasma concentrations have been studied in 10 cystic fibrosis patients suffering from chronic pulmonary infections with Pseudomonas aeruginosa. Patients were given single i.v. doses of 100 e 200 mg/kg body weight as intravenous infusion over 30 minutes. Azlocillin plasma levels have been assayed by a rapid, sensitive and precise high performance liquid chromatographic method. After the dose of 100 mg/kg body weight concentrations of azlocillin decreased below the therapeutic concentrations after three hours; dose of 200 mg/kg was followed by plasma concentrations in the therapeutically desirable range during the 6-8 hours study period. The pharmacokinetic analysis offers further evidence of the dose-dependent nature of azlocillin elimination. Higher dosage of 200 mg/kg body weight and monitoring of plasma drug levels are recommended in the therapy of patients with cystic fibrosis.

Netilmicin sulfate as single-agent therapy for Pseudomonas infections.

In a prospective multicenter clinical trial, 69 patients with Pseudomonas infections were treated with netilmicin sulfate as the only antipseudomonal antibiotic. Clinical resolution or improvement was observed for 81% of the infections, whereas 19% were considered treatment failures. The bacteriologic response, based on follow-up culture results, showed elimination of Pseudomonas from 62% of the infection sites, with persistence in 30%. All isolates were susceptible by disk susceptibility testing (zone greater than or equal to 15 mm), and by microdilution testing in unsupplemented broth. The majority of isolates, however, were resistant in cation supplemented media. The clinical failures could be accounted for by factors other than netilmicin failure. In conclusion, netilmicin appeared effective as treatment for netilmicin-susceptible Pseudomonas infections in nonneutropenic adults. A low incidence of nephrotoxicity (12%) occurred despite careful monitoring of serum levels.

Efficacy of ciprofloxacin in experimental aortic valve endocarditis caused by a multiply beta-lactam-resistant variant of Pseudomonas aeruginosa stably derepressed for beta-lactamase production.

The emergence of multi-beta-lactam resistance is a limiting factor in treating invasive Pseudomonas infections with newer cephalosporins. The in vivo efficacy of ciprofloxacin, a new carboxy-quinolone, was evaluated in experimental aortic valve endocarditis caused by a strain of Pseudomonas aeruginosa which is stably derepressed for beta-lactamase production and is resistant to ceftazidime and multiple other beta-lactam agents. A total of 51 catheterized rabbits with aortic catheters in place were infected with this strain and then received no therapy (controls), ceftazidime (75 mg/kg per day), or ciprofloxacin (80 mg/kg per day). Ciprofloxacin sterilized all blood cultures and significantly lowered vegetation densities of P. aeruginosa by day 2 of treatment versus controls (P less than 0.0005) and animals receiving ceftazidime (P less than 0.0005). This beneficial effect of ciprofloxacin was also noted on therapy days 6 and 11. Ciprofloxacin rendered most vegetations (85%) culture negative over the 11-day treatment period and achieved bacteriologic cure in 73% of animals (P less than 0.0005 versus other therapy groups). Ciprofloxacin prevented bacteriologic relapse at 6 days posttherapy. No ciprofloxacin resistance was detected among Pseudomonas isolates from cardiac vegetations. Ciprofloxacin warrants further evaluation in vivo versus multi-drug-resistant gram-negative bacillary infections.

Essential element nutritional status in cystic fibrosis.

Serum calcium, magnesium, iron, copper and zinc were measured in 117 patients with cystic fibrosis. Apart from serum iron levels, all the other essential element levels were well maintained and there was no evidence of a need for supplementation. Serum iron was frequently low and the need for iron supplements must be considered after further investigation. The subjects studied covered a wide age range, had widely varying fat malabsorption and clinical grading, and also varying degrees of pulmonary involvement. We found no evidence that any of these parameters directly influenced essential element status as assessed by serum levels.

A randomized study of tobramycin plus ticarcillin, tobramycin plus cephalothin and ticarcillin, or tobramycin plus mezlocillin in the treatment of infection in neutropenic patients with malignancies.

Two hundred twenty-five patients with 358 febrile episodes were treated with tobramycin and ticarcillin (TT), tobramycin and mezlocillin (TM), or tobramycin, ticarcillin and cephalothin (TTC). There were no statistically significant differences in the response rates for patients who were proven to have infection (67% with TT, 69% with TTC and 53% with TM). Patients were more often cured of their infection if their neutrophil count rose during therapy. In this study, the addition of cephalothin to TT did not increase the frequency of azotemia (10% and 12%, respectively). Although mezlocillin has a broader spectrum of activity in vitro than ticarcillin, it was not more efficacious when combined with tobramycin than ticarcillin plus tobramycin for the treatment of infections in neutropenic patients.

Relationship between gentamicin susceptiblity criteria and therapeutic serum levels for Pseudomonas aeruginosa in mouse infection model.

In this study estimations of in vivo and in vitro gentamicin susceptibility for a series of strains of Pseudomonas aeruginosa were compared. The series included an extremely susceptible strain, typically susceptible strains by current susceptibility criteria, and strains with enzymatic and permeability-mediated resistance. In vivo testing was done by using a mice protection test involving six 1-h doses of gentamicin and an inoculum of 50 50% lethal doses of P. aeruginosa. Both normal mice and cyclophosphamide-treated mice were used. It was found that peak serum levels and serum levels of gentamicin obtained just prior to the sixth dose (fifth dose trough levels) required for protection were much higher than minimal inhibitory concentrations (MICs) or minimal bactericidal concentrations (MBCs) obtained in high-cation medium. However, first dose trough levels were similar to MICs or MBCs. Only an extremely susceptible strain, 280, could be treated at antibiotic dosages and serum levels which are considered likely to be safe in humans. A distinct inoculum effect was found in the mice tests, with a 10-fold increase in inoculum producing a 4-fold increase in the amount of gentamicin required, but no inoculum effect was found for MICs. These results suggest that current susceptibility criteria in use for gentamicin and P. aeruginosa overestimate gentamicin susceptibility, particularly when low-cation growth medium is used for susceptibility testing and when treating disseminated infection.

Clinical and laboratory studies with amikacin in newborns, infants, and children.

Thirty (86%) of 35 infants and older children with proven gram-negative sepsis had a complete clinical remission after treatment with amikacin. In 27 (82%) of 33 infectious episodes for which bacteriologic results were available before and after treatment, the organism was eradicated. The dosage of amikacin was either 7.5 mg/kg or 15 mg/kg given intramuscularly at 12-hr intervals. No adverse clinical effects or laboratory abnormalities were observed during treatment, which lasted from five to 14 days. All bacteria were sensitive to amikacin when tested by the disk diffusion method, and all but a single strain of Pseudomonas were sensitive when tested by the agar dilution method. Assays of serum and urine demonstrated adequate levels of amikacin after single intramuscular injections of 3.75 or 7.5 mg/kg; simultaneous assays of serum and cerebrospinal fluid in two cases demonstrated comparable concentrations of drug suggestive of a high degree of penetration into the cerebrospinal fluid in two cases demonstrated comparable concentrations of drug suggestive of a high degree of penetration into the cerebrospinal fluid during infection. Serial measurements of amikacin in serum from 0.5 to 12 hr after administration of single doses of 7.5 mg of drug/kg to six newborns revealed no significant differences in the concentrations achieved with intramuscular or intravenous administration of the drug.

Amikacin therapy for severe gram-negative sepsis: efficacy in infections involving gentamicin-resistant organisms.

Thirty-eight patients with 41 serious infections due to gram-negative bacteria were treated with amikacin. Twenty of these infections involved organisms that were resistant to gentamicin. The results of therapy in 31 of the infections satisfied the criteria for bacteriologic and clinical cure. Eight patients with urinary tract infections and obstructive uropathy had a good clinical response, but routine follow-up cultures of urine at 30 days were positive. Two patients had persistent sepsis and were considered therapeutic failures. Toxicity to the eighth nerve was documented in three of 31 patients for whom routine audiometric testing was performed. These results indicate that amikacin is effective in the treatment of serious infections due to gram-negative bacilli and is particularly useful in infections involving resistant organisms.